JP5933902B2 - Trkaキナーゼ阻害剤としてのピロリジニル尿素およびピロリジニルチオ尿素化合物 - Google Patents
Trkaキナーゼ阻害剤としてのピロリジニル尿素およびピロリジニルチオ尿素化合物 Download PDFInfo
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- JP5933902B2 JP5933902B2 JP2014510416A JP2014510416A JP5933902B2 JP 5933902 B2 JP5933902 B2 JP 5933902B2 JP 2014510416 A JP2014510416 A JP 2014510416A JP 2014510416 A JP2014510416 A JP 2014510416A JP 5933902 B2 JP5933902 B2 JP 5933902B2
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- Prior art keywords
- alkyl
- alkoxy
- independently selected
- optionally substituted
- hetar
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- LUZJFNYVKQEEGM-UHFFFAOYSA-N pyrrolidin-1-ylthiourea Chemical class NC(=S)NN1CCCC1 LUZJFNYVKQEEGM-UHFFFAOYSA-N 0.000 title description 2
- MZVRPCYUUFGMLJ-UHFFFAOYSA-N pyrrolidin-1-ylurea Chemical compound NC(=O)NN1CCCC1 MZVRPCYUUFGMLJ-UHFFFAOYSA-N 0.000 title description 2
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 title 1
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 title 1
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 1238
- 125000003545 alkoxy group Chemical group 0.000 claims description 703
- 150000001875 compounds Chemical class 0.000 claims description 287
- -1 hydroxyl-carbonyl Chemical group 0.000 claims description 259
- 229910052736 halogen Inorganic materials 0.000 claims description 171
- 150000002367 halogens Chemical class 0.000 claims description 169
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 160
- 239000000203 mixture Substances 0.000 claims description 121
- 238000002360 preparation method Methods 0.000 claims description 119
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 104
- 238000000034 method Methods 0.000 claims description 97
- 125000005842 heteroatom Chemical group 0.000 claims description 89
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 84
- 229910052760 oxygen Inorganic materials 0.000 claims description 83
- 229910052739 hydrogen Inorganic materials 0.000 claims description 82
- 208000002193 Pain Diseases 0.000 claims description 81
- 125000001424 substituent group Chemical group 0.000 claims description 81
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 78
- 150000003839 salts Chemical class 0.000 claims description 77
- 229910052717 sulfur Inorganic materials 0.000 claims description 76
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 72
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 69
- 229920006395 saturated elastomer Polymers 0.000 claims description 68
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 63
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 55
- 125000000623 heterocyclic group Chemical group 0.000 claims description 53
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 46
- 239000012453 solvate Substances 0.000 claims description 41
- 206010028980 Neoplasm Diseases 0.000 claims description 40
- 125000004429 atom Chemical group 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 238000011282 treatment Methods 0.000 claims description 38
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 36
- 201000011510 cancer Diseases 0.000 claims description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
- 125000002252 acyl group Chemical group 0.000 claims description 33
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 32
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 32
- 125000004414 alkyl thio group Chemical group 0.000 claims description 26
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 22
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 21
- 241000124008 Mammalia Species 0.000 claims description 20
- 230000004770 neurodegeneration Effects 0.000 claims description 20
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 125000004950 trifluoroalkyl group Chemical group 0.000 claims description 19
- 206010061218 Inflammation Diseases 0.000 claims description 18
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 18
- 230000004054 inflammatory process Effects 0.000 claims description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 230000008878 coupling Effects 0.000 claims description 17
- 238000010168 coupling process Methods 0.000 claims description 17
- 238000005859 coupling reaction Methods 0.000 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 208000000094 Chronic Pain Diseases 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims description 14
- 208000005298 acute pain Diseases 0.000 claims description 12
- 208000035475 disorder Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 11
- 206010001935 American trypanosomiasis Diseases 0.000 claims description 10
- 208000024699 Chagas disease Diseases 0.000 claims description 10
- 208000004296 neuralgia Diseases 0.000 claims description 10
- 208000021722 neuropathic pain Diseases 0.000 claims description 10
- 125000006413 ring segment Chemical group 0.000 claims description 10
- 206010065390 Inflammatory pain Diseases 0.000 claims description 9
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 9
- 125000002837 carbocyclic group Chemical group 0.000 claims description 9
- 238000001356 surgical procedure Methods 0.000 claims description 9
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 125000004422 alkyl sulphonamide group Chemical group 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 5
- SIISYXWWQBUDOP-UHFFFAOYSA-N bis(1h-imidazol-2-yl)methanethione Chemical compound N=1C=CNC=1C(=S)C1=NC=CN1 SIISYXWWQBUDOP-UHFFFAOYSA-N 0.000 claims description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 claims 1
- 238000003419 tautomerization reaction Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 138
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 125
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- 239000000243 solution Substances 0.000 description 81
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 70
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 63
- 239000007787 solid Substances 0.000 description 62
- 235000019439 ethyl acetate Nutrition 0.000 description 60
- 239000000047 product Substances 0.000 description 60
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- 125000004432 carbon atom Chemical group C* 0.000 description 49
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- 239000000725 suspension Substances 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 34
- 238000005481 NMR spectroscopy Methods 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000012267 brine Substances 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- 239000002585 base Substances 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 25
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 25
- 239000003921 oil Substances 0.000 description 25
- 235000019198 oils Nutrition 0.000 description 25
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 24
- 239000000377 silicon dioxide Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 125000003226 pyrazolyl group Chemical group 0.000 description 21
- 239000004215 Carbon black (E152) Substances 0.000 description 18
- 239000000284 extract Substances 0.000 description 18
- 229930195733 hydrocarbon Natural products 0.000 description 18
- 239000010410 layer Substances 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 17
- 108010025020 Nerve Growth Factor Proteins 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- 101150111783 NTRK1 gene Proteins 0.000 description 14
- 125000002098 pyridazinyl group Chemical group 0.000 description 14
- 150000003254 radicals Chemical class 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 13
- 229940067157 phenylhydrazine Drugs 0.000 description 13
- 125000000335 thiazolyl group Chemical group 0.000 description 13
- 125000002883 imidazolyl group Chemical group 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 12
- 125000001544 thienyl group Chemical group 0.000 description 12
- 208000005615 Interstitial Cystitis Diseases 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 11
- 125000002971 oxazolyl group Chemical group 0.000 description 11
- 125000001113 thiadiazolyl group Chemical group 0.000 description 11
- MXZMACXOMZKYHJ-UHFFFAOYSA-N 4,4-dimethyl-3-oxopentanenitrile Chemical group CC(C)(C)C(=O)CC#N MXZMACXOMZKYHJ-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000013058 crude material Substances 0.000 description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 10
- 125000000842 isoxazolyl group Chemical group 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 125000003373 pyrazinyl group Chemical group 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 125000001425 triazolyl group Chemical group 0.000 description 10
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- QRMHDGWGLNLHMN-UHFFFAOYSA-N Methyl methoxyacetate Chemical compound COCC(=O)OC QRMHDGWGLNLHMN-UHFFFAOYSA-N 0.000 description 9
- 229910004298 SiO 2 Inorganic materials 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 239000012265 solid product Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- NTOIKDYVJIWVSU-WOJBJXKFSA-N (2r,3r)-2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)[C@@](O)(C(O)=O)[C@](O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 NTOIKDYVJIWVSU-WOJBJXKFSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- 102000015336 Nerve Growth Factor Human genes 0.000 description 8
- 102000007072 Nerve Growth Factors Human genes 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 229940043279 diisopropylamine Drugs 0.000 description 8
- 125000002541 furyl group Chemical group 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 125000002757 morpholinyl group Chemical group 0.000 description 8
- 229940053128 nerve growth factor Drugs 0.000 description 8
- 125000003386 piperidinyl group Chemical group 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000006188 syrup Substances 0.000 description 8
- 235000020357 syrup Nutrition 0.000 description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- 125000002393 azetidinyl group Chemical group 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 208000037765 diseases and disorders Diseases 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 229910052740 iodine Inorganic materials 0.000 description 7
- 125000001715 oxadiazolyl group Chemical group 0.000 description 7
- 229930195734 saturated hydrocarbon Natural products 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 230000001684 chronic effect Effects 0.000 description 6
- HAHYIMGJWDNBDK-UHFFFAOYSA-N ethyl 3-hydrazinylbenzoate Chemical compound CCOC(=O)C1=CC=CC(NN)=C1 HAHYIMGJWDNBDK-UHFFFAOYSA-N 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 125000001786 isothiazolyl group Chemical group 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 6
- 239000002480 mineral oil Substances 0.000 description 6
- 235000010446 mineral oil Nutrition 0.000 description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
- 125000004193 piperazinyl group Chemical group 0.000 description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 description 6
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 6
- 229910052727 yttrium Inorganic materials 0.000 description 6
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 5
- IWWQROMVQSKLDE-UHFFFAOYSA-N 2-methoxy-n-(methoxymethyl)-n-(trimethylsilylmethyl)ethanamine Chemical compound COCCN(COC)C[Si](C)(C)C IWWQROMVQSKLDE-UHFFFAOYSA-N 0.000 description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 4
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 4
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 4
- 208000035473 Communicable disease Diseases 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 4
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
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Classifications
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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JP2016501191A (ja) * | 2012-11-13 | 2016-01-18 | アレイ バイオファーマ、インコーポレイテッド | Trkaキナーゼ阻害剤としてのn−ピロリジニル、n’−ピラゾリル尿素、チオ尿素、グアニジン、およびシアノグアニジン化合物 |
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EP2116539A1 (en) | 2008-04-25 | 2009-11-11 | Laboratorios Del. Dr. Esteve, S.A. | 1-aryl-3-aminoalkoxy-pyrazoles as sigma ligands enhancing analgesic effects of opioids and attenuating the dependency thereof |
RS53350B (en) | 2008-09-22 | 2014-10-31 | Array Biopharma, Inc. | SUBSTITUTED COMPOUNDS OF IMIDASO [1,2-B] PYRIDASINE AS INK KINASE INHIBITORS |
SI3372605T1 (sl) | 2008-10-22 | 2022-03-31 | Array Biopharma, Inc. | Substituirane pirazolo(1,5-a)pirimidinske spojine kot zaviralci TRK-kinaze |
AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
EP2353591A1 (en) | 2010-02-04 | 2011-08-10 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof |
EP2353598A1 (en) | 2010-02-04 | 2011-08-10 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for use in the prevention and/or treatment of postoperative pain |
EP3521291A1 (en) | 2010-05-20 | 2019-08-07 | Array Biopharma, Inc. | Macrocyclic compounds as trk kinase inhibitors |
EP2388005A1 (en) | 2010-05-21 | 2011-11-23 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy |
EP2415471A1 (en) | 2010-08-03 | 2012-02-08 | Laboratorios Del. Dr. Esteve, S.A. | Use of sigma ligands in opioid-induced hyperalgesia |
ME02583B (me) | 2011-05-13 | 2017-06-20 | Array Biopharma Inc | Jedinjenja pirolidinil uree, pirolidinil tiouree i pirolidinil guanidina kao inhibitori trka kinaze |
EP2524694A1 (en) | 2011-05-19 | 2012-11-21 | Laboratorios Del. Dr. Esteve, S.A. | Use of sigma ligands in diabetes type-2 associated pain |
WO2014078325A1 (en) * | 2012-11-13 | 2014-05-22 | Array Biopharma Inc. | N-(monocyclic aryl),n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors |
WO2014078408A1 (en) | 2012-11-13 | 2014-05-22 | Array Biopharma Inc. | Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors |
WO2014078322A1 (en) | 2012-11-13 | 2014-05-22 | Array Biopharma Inc. | Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors |
WO2014078417A1 (en) * | 2012-11-13 | 2014-05-22 | Array Biopharma Inc. | Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors |
WO2014078372A1 (en) * | 2012-11-13 | 2014-05-22 | Array Biopharma Inc. | Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors |
WO2014078378A1 (en) * | 2012-11-13 | 2014-05-22 | Array Biopharma Inc. | Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors |
US9546156B2 (en) | 2012-11-13 | 2017-01-17 | Array Biopharma Inc. | N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors |
US9969694B2 (en) | 2012-11-13 | 2018-05-15 | Array Biopharma Inc. | N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors |
LT2920166T (lt) | 2012-11-13 | 2016-12-12 | Array Biopharma, Inc. | Bicikliniai karbamido, tiokarbamido, guanidino ir cianoguanidino junginiai, tinkami naudoti skausmo gydymui |
CA2896187A1 (en) | 2013-01-18 | 2014-07-24 | F. Hoffmann-La Roche Ag | 3-substituted pyrazoles and use as dlk inhibitors |
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JP2016501191A (ja) * | 2012-11-13 | 2016-01-18 | アレイ バイオファーマ、インコーポレイテッド | Trkaキナーゼ阻害剤としてのn−ピロリジニル、n’−ピラゾリル尿素、チオ尿素、グアニジン、およびシアノグアニジン化合物 |
JP2018048176A (ja) * | 2012-11-13 | 2018-03-29 | アレイ バイオファーマ、インコーポレイテッド | Trkaキナーゼ阻害剤としてのn−ピロリジニル、n’−ピラゾリル尿素、チオ尿素、グアニジン、およびシアノグアニジン化合物 |
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